REVIEW
published: 26 October 2021
doi: 10.3389/fphys.2021.770455
Mechanisms Linking the Gut-Muscle
Axis With Muscle Protein Metabolism
and Anabolic Resistance:
Implications for Older Adults at Risk
of Sarcopenia
Konstantinos Prokopidis 1* , Edward Chambers 2 , Mary Ni Lochlainn 3 and
Oliver C. Witard 4
1
Department of Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool,
United Kingdom, 2 Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College, London,
United Kingdom, 3 Department of Twin Research and Genetic Epidemiology, King’s College London, London,
United Kingdom, 4 Faculty of Life Sciences and Medicine, Centre for Human and Applied Physiological Sciences, King’s
College London, London, United Kingdom
Edited by:
Llion Arwyn Roberts,
Griffith University, Australia
Reviewed by:
Andrea Ticinesi,
University of Parma, Italy
Sergio Perez-Burillo,
University of Granada, Spain
*Correspondence:
Konstantinos Prokopidis
k.prokopidis@liverpool.ac.uk
Specialty section:
This article was submitted to
Integrative Physiology,
a section of the journal
Frontiers in Physiology
Received: 06 September 2021
Accepted: 07 October 2021
Published: 26 October 2021
Citation:
Prokopidis K, Chambers E,
Ni Lochlainn M and Witard OC (2021)
Mechanisms Linking the Gut-Muscle
Axis With Muscle Protein Metabolism
and Anabolic Resistance: Implications
for Older Adults at Risk of Sarcopenia.
Front. Physiol. 12:770455.
doi: 10.3389/fphys.2021.770455
Frontiers in Physiology | www.frontiersin.org
Aging is associated with a decline in skeletal muscle mass and function—termed
sarcopenia—as mediated, in part, by muscle anabolic resistance. This metabolic
phenomenon describes the impaired response of muscle protein synthesis (MPS) to
the provision of dietary amino acids and practice of resistance-based exercise. Recent
observations highlight the gut-muscle axis as a physiological target for combatting
anabolic resistance and reducing risk of sarcopenia. Experimental studies, primarily
conducted in animal models of aging, suggest a mechanistic link between the gut
microbiota and muscle atrophy, mediated via the modulation of systemic amino acid
availability and low-grade inflammation that are both physiological factors known to
underpin anabolic resistance. Moreover, in vivo and in vitro studies demonstrate the
action of specific gut bacteria (Lactobacillus and Bifidobacterium) to increase systemic
amino acid availability and elicit an anti-inflammatory response in the intestinal lumen.
Prospective lifestyle approaches that target the gut-muscle axis have recently been
examined in the context of mitigating sarcopenia risk. These approaches include
increasing dietary fiber intake that promotes the growth and development of gut
bacteria, thus enhancing the production of short-chain fatty acids (SCFA) (acetate,
propionate, and butyrate). Prebiotic/probiotic/symbiotic supplementation also generates
SCFA and may mitigate low-grade inflammation in older adults via modulation of the
gut microbiota. Preliminary evidence also highlights the role of exercise in increasing
the production of SCFA. Accordingly, lifestyle approaches that combine diets rich in
fiber and probiotic supplementation with exercise training may serve to produce SCFA
and increase microbial diversity, and thus may target the gut-muscle axis in mitigating
anabolic resistance in older adults. Future mechanistic studies are warranted to establish
the direct physiological action of distinct gut microbiota phenotypes on amino acid
utilization and the postprandial stimulation of muscle protein synthesis in older adults.
Keywords: anabolic resistance, sarcopenia, gut microbiota, dietary fiber, skeletal muscle, exercise
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Anabolic Resistance and Gut Microbiota
in regulating the utilization of amino acids (Yatsunenko et al.,
2012; Ticinesi et al., 2019). In this regard, gut microbiota
dysbiosis (Mahnic et al., 2020) is a physiological phenomenon
that describes an altered gut microbiota composition (Biagi
et al., 2010; Odamaki et al., 2016) and diversity (Nagpal et al.,
2018; Coman and Cristian, 2020), and is proposed as another
mediator of age-related AR. Further evidence also exists that an
altered gut microbiota may directly increase risk of sarcopenia
through specific bacterial depletion and fecal transplantation
(Liu et al., 2021). Hence, the aims of this opinion narrative
review are two-fold. First, to offer hypothesis-driven insights into
possible pathophysiological mechanisms linking gut microbiota
dysbiosis with impaired skeletal muscle metabolism in older
adults. Second, and based on limited existing evidence, to
propose a series of potential, non-pharmacological, strategies
targeted at combatting AR via modulation of the gut microbiota.
Interventional approaches addressed in this narrative review
are by no means exhaustive and are focused on dietary fiber
consumption, probiotic and prebiotic supplementation, and
resistance exercise training.
INTRODUCTION
Sarcopenia is described as the age-related decline in skeletal
muscle mass and function (Rosenberg, 1997) that was recently
recognized as an independent geriatric condition (Cao and
Morley, 2016) and is reported to affect 8–13% of older
adults (Shafiee et al., 2017). Although aging is associated
with a progressive decline in muscle mass and strength, an
accelerated deterioration of muscle functional capacity has been
observed in individuals with sarcopenia (Cruz-Jentoft et al.,
2019). The clinical implications of sarcopenia include—but are
not limited to—an increased incidence of falls and fractures,
frailty, loss of mobility and independence, and premature
mortality among older adults (Cruz-Jentoft et al., 2019). Hence,
understanding the interplay between physiological mechanisms
that underpin sarcopenia is fundamental to developing targeted
and effective lifestyle approaches to reduce sarcopenia risk in our
aging population.
Multiple physiological factors are proposed to underpin
sarcopenia. These factors include—but are not limited to—agerelated changes in hormonal milieu (Sakuma and Yamaguchi,
2012), and gut physiology (Azzolino et al., 2019), a chronic state
of low-grade inflammation (Beyer et al., 2012), insulin resistance
(Cleasby et al., 2016), DNA damage, elevated oxidative stress,
mitochondrial dysfunction (Jackson and McArdle, 2016), and
suppressed satellite cell activity (Snijders et al., 2015), as reviewed
previously (von Haehling et al., 2012). Ultimately, muscle atrophy
is underpinned by a state of negative muscle protein balance
whereby rates of muscle protein breakdown (MPB) exceed rates
of muscle protein synthesis (MPS) over a given period of time.
Of these two metabolic processes, there is general consensus
that a diminished capacity for older adults to stimulate MPS,
as opposed to an acceleration of MPB, mediates muscle atrophy
with aging, at least in healthy individuals (Tipton et al., 2018).
In this regard, whereas comparative studies of young and older
adults have reported no clear differences in basal postabsorptive
rates of MPS, an impaired response of MPS to ingestion of meallike quantities of protein (Guillet et al., 2004; Cuthbertson et al.,
2005; Moore et al., 2015) and/or other anabolic stimuli such as
resistance exercise (Kumar et al., 2009; Durham et al., 2010) have
been consistently reported with advanced age. This metabolic
phenomenon has been coined muscle anabolic resistance (AR)
and is proposed to contribute to the progressive decline in skeletal
muscle mass associated with aging.
The physiological mechanisms that mediate AR are multifactorial but, to this end, are not fully understood (Burd et al.,
2012). Fundamentally, the diminished capacity for older adults to
stimulate MPS is underpinned by a reduced systemic (Bohé et al.,
2003) and/or intracellular availability of amino acids (Kimball
and Jefferson, 2002). Physiological processes that contribute to
this age-related decline in amino acid availability include an
increased splanchnic retention of amino acids leading to reduced
peripheral amino acid availability (Boirie et al., 1997), a reduction
in amino acid transport to muscle tissue (Biolo et al., 1995), and
an impairment in microvascular perfusion (capillary recruitment
and dilation) (Phillips et al., 2015). Recent evidence also indicates
an important role for the human gut microbiota environment
Frontiers in Physiology | www.frontiersin.org
GUT MICROBIOTA IN AGING
The structure and diversity of the human gut microbiome
plays a key regulatory role in physiological, metabolic, and
immune function, and thus impacts human health and
disease risk (Guinane and Cotter, 2013). Specifically, the gut
microbiome contains millions of diverse microorganisms,
termed gut microbiota, that modulate various metabolic
pathways, including inflammatory gene expression, innate
immune effector cells (i.e., monocytes, macrophages), glucose
tolerance, and the release of gut hormones (Martin et al.,
2019; Zheng et al., 2020). The multiple microbial phyla of
the gut microbiome include Proteobacteria, Fusobacteria,
Actinobacteria, Verrucomicrobia, Firmicutes (Clostridium,
Enterococcus, Ruminococcus, Lactobacillus), and Bacteroidetes
(Prevotella, Bacteroides), and account for the majority of the
microbiota species present in the gut (Wang et al., 2020),
although several bacterial species may be found in other
organs including muscle, brain, liver, heart, and adipose tissue
(Lluch et al., 2015).
The composition of gut microbiota is modulated by several
factors including genetics, diet and physical activity levels
(Milani et al., 2016; Ticinesi et al., 2017). Aging also is
strongly associated with a decline in gut microbiome diversity
species in the duodenum, jejunum, ileum, and colon (Sovran
et al., 2019; Badal et al., 2020). Taxonomic differences during
aging have been observed, namely that older adults are
accompanied by higher levels of Bacteroides, Eubacterium,
and Clostridiaceae, and decreased Bifidobacterium compared to
young adults (Yatsunenko et al., 2012; Odamaki et al., 2016;
Stewart et al., 2018). During the aging process, epithelial cell
tight junctions are weakened (Lustgarten, 2016), decreasing the
expression of intestinal epithelial tight junctions proteins (Tran
and Greenwood-Van Meerveld, 2013). This disrupted intestinal
barrier is linked to reduced intestinal motility and increased
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Anabolic Resistance and Gut Microbiota
Roseburia inulinivorans, and Alistipes shahii species that are
all competent bacteria with prominent metabolic capacity
in producing SCFA (Ticinesi et al., 2020). The 16S rRNA
sequencing of human fecal samples from (pre)sarcopenic
individuals showed a decline in Lachnospira, Fusicantenibacter,
Roseburia, Eubacterium, and Lachnostrodium genera, and an
increased LPS biosynthesis compared to healthy individuals
(Kang et al., 2021). Taken together, these data indicate a link
between the gut microbiota and muscle atrophy, and thus
supports a gut-muscle axis hypothesis to explain, in part, skeletal
muscle dysfunction during aging.
permeability, that are associated with higher levels of low-grade
inflammation and immunosenescence that accompany various
age-associated conditions (Belkaid and Hand, 2014; Bosco and
Noti, 2021). Therefore, the various taxonomic changes that
occur over time via altered microbial function and composition
may affect immune and metabolic health with advancing age
(Ling et al., 2020).
THE GUT-MUSCLE AXIS IN
SARCOPENIA
Multiple lines of evidence from rodent studies suggest that
the gut microbiota may be linked with sarcopenia. First, the
microbiota of older mice was shown to exhibit an abundance
of the Rikenellaceae family that is associated with an increased
frailty index in a dose-dependent manner (Langille et al., 2014).
Second, a higher Sutterella to Barneseilla ratio has been reported
in older sarcopenic vs. healthy adult rats, corresponding with an
altered inflammatory and immune profile and decline in triceps
and gastrocnemius size (Siddharth et al., 2017). Third, germfree mice that lack the gut microbiota of pathogen-free mice
exhibit a greater decline in skeletal muscle mass, quality and
neuromuscular function compared to pathogen-free mice (Lahiri
et al., 2019), despite having similar body weight (Hsu et al., 2015).
Finally, antibiotic-treated mice were accompanied by increased
muscle atrophy (Manickam et al., 2018; Nay et al., 2019; Okamoto
et al., 2019), that was associated with microbial dysbiosis and
inhibition of ileal fibroblast growth factor 15 (FGF15), whereas
muscle atrophy was reversed following FGF19 treatment (Qiu
et al., 2021). Hence, some mechanistic evidence exists in animal
models that the gut microbiome may play a key role in physical
performance, given that germ-free and antibiotic-treated mice
express lower competence during muscle loading (Lahiri et al.,
2019) and swimming time to exhaustion (Hsu et al., 2015; Huang
et al., 2019), compared to pathogen-free mice.
The hypothesis that the gut microbiota may be linked with
sarcopenia has also been examined in humans. Using 16s
RNA sequencing, a higher abundance of Lactobacillus and
a reduction of Fusicantenibacter, Eubacterium, Lachnospira,
Lachnoclostridium, and Roseburia genera was reported in
sarcopenic patients compared with healthy controls (Kang et al.,
2021). In addition, cross-sectional studies have revealed a higher
ratio of Firmicutes/Bacteoidetes and lower overall microbial
richness in older adult patient groups compared with healthy
young adult controls (Mariat et al., 2009; Larsen et al., 2010;
Claesson et al., 2012; Le Chatelier et al., 2013). Accordingly,
a higher abundance of several bacteria, including Eggerthella,
Bacteroides/Prevotella, Lactobacillus/Enterococcus, and a lower
abundance of Enterobacteriaceae, Methanobrevibacter, and
Akkermansia, have been observed in frail patient groups
(Van Tongeren et al., 2005; Ponziani et al., 2021). Moreover,
in sarcopenic and physically frail populations, an increased
abundance of Oscillospira and Ruminococcus, and a decrease
of Barnesiellacaea and Christensenellaceae taxa also have been
reported (Picca et al., 2020). Similarly, sarcopenic patients
displayed a significant reduction in Faecalibacterium prausnitzii,
Frontiers in Physiology | www.frontiersin.org
GUT MICROBIOTA AND ANABOLIC
RESISTANCE
The gut microbiota also is proposed to play a causal role in AR
(Frampton et al., 2020), as mediated by multiple inter-related
physiological mechanisms (Figure 1). The causal mechanisms
that underpin AR span several levels of physiology, including
the gut, vascular system, and skeletal muscle (Burd et al.,
2013). Altered gut microbiota composition during aging may
be involved in oxidative stress, inflammation, and insulin
resistance (Grosicki et al., 2018). An aging gut microbiota
may increase intestinal permeability and LPS leakage from
the intestinal lumen and cell membranes of gram-negative
bacteria into the circulation (Maes et al., 2012; Alhmoud
et al., 2019). Such modifications are associated with insulin
resistance and increased inflammation (Liang et al., 2013;
Choi et al., 2015; Moszak et al., 2020), both of which are
physiological factors linked with increased risk of sarcopenia
(Nelke et al., 2019; Shou et al., 2020). Older adults are
characterized by increased LPS levels that enhance toll-like
receptor 4 (TLR4) signaling, promoting metabolic endotoxemia
(Ghosh et al., 2015). Metabolic endotoxemia may induce systemic
inflammation through reactive oxygen species production (Yuan
et al., 2013) and activation of apoptotic pathways (i.e., nuclear
factor κB, c-Jun N-terminal kinase), downregulating immune
function in older adults (Qian et al., 2012). Specifically,
proinflammatory cytokines (i.e., IL-6 and TNF-a) may modulate
LPS-induced proinflammatory responses through TLR4/Mal
signaling pathway (Greenhill et al., 2011). Therefore, the altered
function and composition of gut metabolites during aging
may be responsible for metabolic perturbations that develop
throughout lifespan.
Regarding gut physiology, amino acid absorption is
modulated at the cellular level via active transport by the
epithelial intestinal cells in the small intestine located at
the surface of enterocytes (Mardinoglu et al., 2015). These
transporters shuttle amino acids into the circulation (Broer,
2008) via the peptide transporter 1 carrier (Walther et al., 2019).
Recent evidence implicates a role for the human microbial
environment in amino acid homeostasis (Yatsunenko et al., 2012;
Ticinesi et al., 2019). Specifically, human studies demonstrate
that the microbial-derived amino acids, e.g., threonine and
lysine, are incorporated into the free plasma amino acid pool
following consumption of a moderate protein diet, suggesting
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Anabolic Resistance and Gut Microbiota
FIGURE 1 | Proposed mechanisms that underpin muscle anabolic resistance via changes in gut microbiota diversity.
targeted at modulating the microbial environment may mitigate
AR associated with sarcopenia.
that disruption of the gut microbiota environment may suppress
the microbial-induced production of amino acids (Metges
et al., 1999) and potentially lead to AR. Furthermore, during
dietary protein restriction, the gut microbiota is reported to
produce amino acids through de novo biosynthesis (Lin et al.,
2017) and is implicated in amino acid homeostasis via FGF21
hepatic signaling (Martin et al., 2021). However, the role of the
gut microbiome in modulating the uptake of amino acids, in
particular the branched-chain amino acids, into the skeletal
muscle cell is yet to be fully elucidated in humans. Future studies
are warranted to fill this gap in knowledge, with the likely
focus on leucine uptake by skeletal muscle given the role of
leucine as both a substrate and signal for the stimulation of MPS
(Anthony et al., 2001).
An alternative mechanism linking the gut microbiota with
AR relates to insulin-like growth factor 1 (IGF-1). IGF-1
synthesis regulates nutrient sensing and the stimulation of MPS
(Bian et al., 2020) that is modulated, in part, by the gut
microbiota (Yan and Charles, 2018). This notion is supported
by previous studies that associated circulating levels of IGF-1
with a decrease in Salmonella typhimurium and Burkholderia
thailandensis infected mice compared to Escherichia coli O21:
H+ treated mice that retained IGF-1/Akt pathway capacity
(Schieber et al., 2015). At the mechanistic level, IGF-1 is
regulatory for muscle growth via the phosphatidylinositol 3kinase (PI3K)/Akt signaling pathway, and serves to suppress the
mRNA transcription and translation process of MPS (Barclay
et al., 2019). A recent study that utilized a 16S ribosomal
RNA gene sequencing approach revealed the gut microbiota of
intestinal epithelial cell-specific IGF-1 knockout mice exhibited
a disrupted intestinal homeostasis and epithelial regeneration
in comparison to mice under normal pathological conditions
(Zheng et al., 2018). Hence, it has been suggested that intestinal
permeability due to microbiota dysbiosis may induce systemic
inflammation (Soendergaard et al., 2017; Thevaranjan et al.,
2017) and suppress IGF-1R sensitivity, thus initiating a catabolic
response through MuRF-1 expression (Barclay et al., 2019).
Given the potential physiological role of the gut microbiota
in regulating skeletal muscle metabolism via the modulation
of amino acid homeostasis and/or IGF-1 activity, a current
focus of physiology research into healthy musculoskeletal aging
relates to optimizing the gut microbiota (Ticinesi et al., 2019;
Ni Lochlainn et al., 2021). It may be considered intuitive that
lifestyle (i.e., physical activity, exercise, and diet) approaches
Frontiers in Physiology | www.frontiersin.org
MICROBIOME-CENTRIC DIETARY
STRATEGIES TO COUNTER ANABOLIC
RESISTANCE
Microbial activity induced by indigestible amino acids promote
the production of metabolic end products including short-chain
fatty acids (SCFA; acetate, butyrate, propionate), branched-chain
fatty acids (BCFA; valerate, isobutyrate, isovalerate), ammines,
phenols, thiols, indoles, and ammonia. SCFA modulate epithelial
cell function and microbiome physiology, serving as the primary
energy source of colonocytes, and thus influence gastrointestinal
health (Canfora et al., 2015). Specifically, acetate is utilized
by skeletal muscle cells for ATP production, whereas the
metabolic fate of butyrate and propionate primarily relates to
gluconeogenesis and cholesterol synthesis (Byrne et al., 2015).
SCFA are produced by dietary fiber fermentation (i.e., resistance
starch, oligofructose, inulin, polydextrose, galactoolisaccharides)
in the colon and are absorbed via the portal vein during lipid
digestion (Chambers et al., 2018b). In addition, bacterial crossfeeding modulates SCFA production and substrate utilization
with regards to human gut physiology (Ríos-Covián et al.,
2016; Tsukuda and Yahagi, 2021). For instance, co-cultured
Bacteroides uniformis and Escherichia coli were more effective
in agarooligosaccharide degradation compared to their isolated
properties (Li et al., 2014). Similarly, Bifidobacterium adolescentis
co-cultured with Bifidobacterium infantis and Roseburia A2-183
strains exhibited a synergistic effect on agarotriose utilization
and butyrate production (Belenguer et al., 2006; Li et al.,
2014). Hence, cross-feeding of bacteria taxa is a primary
contributor of SCFA synthesis and utilization that may
provide useful insight in designing future microbiome-centric
interventions to counter AR.
Several amino acids, including glycine, threonine, glutamate,
lysine, arginine, ornithine, and aspartate, also play an important
role in acetate production, whereas threonine, lysine, and
glutamate are involved in butyrate synthesis, and threonine is
involved in propionate synthesis (Davila et al., 2013). SCFA
are increasingly recognized as modulators of skeletal muscle
metabolism via action of the G protein-coupled receptors
GRP41 (FFAR3) and GRP43 (FFAR2) (Nilsson et al., 2003;
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FIGURE 2 | Proposed role of the gut microbiota in modulating skeletal muscle metabolism under conditions of increased dietary fiber.
this study (Buigues et al., 2016). These observations are in line
with a recent study, highlighting an association of higher dietary
fiber intake with increased skeletal muscle mass and strength in
middle-aged to older adults (Frampton et al., 2021). To date, no
clinical studies have investigated the direct impact of SCFA and
high soluble fiber diets on skeletal muscle protein metabolism.
Hence, future studies are warranted to investigate the chronic
impact of manipulating dietary fiber content in promoting gut
derived SCFA and modulating skeletal muscle metabolism and
inflammation in older adults.
Kimura et al., 2014). GPR41 and GRP43 are understood to
stimulate GLP-1 and PYY secretion and increase insulinmediated glucose uptake in skeletal muscle (Canfora et al., 2015).
In vivo studies have demonstrated improvements in insulin
sensitivity, mitochondrial biogenesis and function, reduced
adiposity, and an increase in type I muscle fiber composition
following SCFA administration (Fushimi et al., 2001; Gao et al.,
2009; Hong et al., 2016; Zhou et al., 2021) that correspond
with an increased myoglobin expression (Yamashita et al.,
2014; Maruta et al., 2016; Figure 2). Accordingly, germfree mice supplemented with SCFA were shown to exhibit
greater muscle (gastrocnemius) mass and strength compared
to germ-free controls (Lahiri et al., 2019). Likewise, a 10week butyrate-enriched diet improved mitochondrial biogenesis,
insulin sensitivity, and muscle (quadriceps and gastrocnemius)
mass in aged mice compared to butyrate-free controls, whereas
no distinguishable differences were observed between younger
groups (Walsh et al., 2015). Collectively, these data imply that
SCFA administration may be beneficial in mitigating AR in mice.
Likewise, in a human study of young and older adults, the
administration of butyrate and propionate was shown to improve
fat oxidation, insulin sensitivity, and inflammatory profiles
(Chambers et al., 2015, 2018a, 2019; Cleophas et al., 2019).
Furthermore, an increased capacity for gut microbial synthesis
of butyrate was associated with elevated Faecalibacterium
prausnitzii and Butyricimonas virosa, and higher skeletal muscle
index (Lv et al., 2021). Interestingly, older adults with a
higher dietary fiber density (grams of fiber consumed/100 kcal)
displayed a positive relationship with increased whole body lean
mass and butyrate-producing bacteria, including Ruminococcus,
Lachnospira, and Clostridia (Barger et al., 2020)] compared
with older adults consuming lower fiber intake. Consistent with
this observation, 13 weeks of soluble fiber supplementation in
older adults led to improvements in handgrip strength, although
changes in gut microbiota and SCFA were not examined in
Frontiers in Physiology | www.frontiersin.org
PREBIOTIC AND PROBIOTIC
SUPPLEMENTATION AS A STRATEGY
TO COUNTER ANABOLIC RESISTANCE
Preliminary evidence, based on a limited number of hypothesisdriven studies, suggests that probiotic supplementation may
confer physiological benefits to host physiology bacteria
and thus promote skeletal muscle anabolism. Several studies
have investigated the impact of Lactobacilli administration
on metabolic function. Specifically, there is evidence that
Lactobacillus plantarum may exert muscle anabolic effects by
enhancing protein assimilation and upregulating the activation
of mTOR as a molecular driver of MPS, as demonstrated using
Drosophila models (Storelli et al., 2011; Erkosar et al., 2015).
This observation may be explained, at least in part, by a shift
in gut microbiota to a higher abundance of butyrate-producing
species, leading to an increased IGF-1 activity and reduced proinflammatory cytokine secretion, as observed in Lactobacillus
supplemented mice compared to germ-free counterparts
(Bindels et al., 2012; Chen et al., 2016, 2020). Furthermore,
administration of Lactobacillus paracasei PS23 resulted in
greater mitochondrial function and reduced inflammatory
cytokine activity in senescence-accelerated mice, with potential
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Anabolic Resistance and Gut Microbiota
implications for reducing sarcopenia risk (Chen et al., 2019).
Consistent with this finding, the administration of probiotics
containing Lactobacilli species was shown to reduce systemic
levels of IL-6 and TNF-a (Barreto et al., 2014; Borzabadi et al.,
2018), and improve amino acid absorption kinetics in humans
(Jäger et al., 2020). Hence, there is physiological rationale, albeit
relatively limited experiential evidence, to suggest that multiple
Lactobacillus strains may mitigate AR through a concomitant
decrease in systemic inflammation and a greater amino acid
utilization in the gut.
The administration of multiple bacterial species may be
another strategy to target the gut microbiota and counteract
AR. Microbiota transplantation from healthy or undernourished
infants into young germ-free mice has demonstrated an
increased accumulation of Ruminococcus gnavus and Clostridium
symbiosum that ameliorated lean body mass gains and muscle
growth (Blanton et al., 2016). Consistent with this observation,
the transfer of gut microbiota from lean vs. obese pigs to germfree coincided with marked increases in gastrocnemius muscle
fiber size (Yan et al., 2016), thus highlighting the potential impact
of administering multiple bacteria through nutritional targets
(i.e., synbiotic supplementation).
The combination of prebiotics (non-digestible fiber) and
probiotics, collectively termed synbiotics, provides an emerging
nutritional strategy to ingest non-digestible fiber in order to
promote the development of specific gut microbiota species.
Synbiotics consist of Bifidobacterium and Lactobacillus species
and have been shown to reduce lipid accumulation, enhance
muscle performance, and improve gut barrier function in aged
mice (Ni et al., 2019). Moreover, synbiotics may suppress lowgrade inflammation through SCFA administration, mediated via
a greater composition of colonic bacteria communities in older
adults (Lahtinen et al., 2009; Macfarlane et al., 2013), although
this observation is not universal (Neto et al., 2013). Accordingly,
probiotic (i.e., Lactobacillus salivarius, Lactobacillus plantarum
TWK10) and prebiotic (i.e., inulin) supplementation has been
proposed as a promising strategy to facilitate the provision of
a healthy gut microbiota, reducing systemic inflammation and
improving exercise performance and muscle strength (Xiao et al.,
2014; Chen et al., 2019; Lee et al., 2020). Consistent with this
notion, several experimental trials have demonstrated microbial
enrichment accompanied by reduced proinflammatory cytokine
secretion (Vulevic et al., 2008), improved insulin sensitivity
(Cani et al., 2009; van der Beek et al., 2018), handgrip strength
(Buigues et al., 2016) and frailty conditions (Theou et al.,
2019), and increased SCFA concentrations (Rebello et al., 2016)
in both young and older adults. Hence, various parameters
(i.e., low-grade inflammation and insulin resistance) associated
with AR may be attenuated with prebiotic, probiotic, and/or
synbiotic administration. To our knowledge, no studies have
investigated the impact of microbial species on the stimulation
of MPS and/or activation of mTOR related signaling in older
adults. Therefore, future studies are warranted to investigate
the impact of prebiotic or probiotic supplementation on the
production of gut microbiota strains and subsequent stimulation
and/or suppression of MPS and MPB, respectively, in young
and older adults.
Frontiers in Physiology | www.frontiersin.org
EXERCISE AS A STRATEGY TO
COUNTER ANABOLIC RESISTANCE VIA
THE MODULATION OF GUT
MICROBIOTA
Exercise/physical activity is a crucial component of any strategy
designed to prevent and/or treat sarcopenia, which may be
mediated, in part, by modulating the gut microbiome (Strasser
et al., 2021). Accordingly, the impact of exercise training in
modulating the gut microbiota has primarily been established
in physically active populations and animal models in the
context of aerobic-based exercise (Cerdá et al., 2016; Taniguchi
et al., 2018; Morita et al., 2019; Przewłócka et al., 2020; Clauss
et al., 2021). Specifically, Bacteroides fragilis gnotobiotic mice
improved swimming exercise capacity and reduced physical
fatigue compared to germ-free mice (Hsu et al., 2015), and
similar results were observed in gnotobiotic models containing
Eubacterium rectale, Lactobacillus plantarum, and Clostridium
coccoides bacteria (Huang et al., 2019). Similarly, inoculation
of Veillonella atypica in mice improved running exercise
capacity and appeared to be mediated via the conversion of
exercise-induced lactate to propionate (Scheiman et al., 2019),
whereas the combination of aerobic exercise with Bifidobacterium
longum administration may further improve aerobic capacity
and inflammatory status as demonstrated in mice supplemented
with a probiotic strain isolated from an elite Olympic athlete
(Huang et al., 2020). Recently, Valentino et al. (2021) showed that
antibiotic-treated mice resulted in a disrupted gut microbiome,
which was correlated with less hypertrophy of soleus type I
and IIa, and plantaris type IIb muscle fibers compared to
untreated counterparts following progressive weighted wheel
running (Valentino et al., 2021). Furthermore, another study
characterized professional athletes as exhibiting more diverse
microbial communities and bacterial species involved in SCFA
production compared to age-matched sedentary individuals
(Barton et al., 2018). This observation may explain the role of
exercise training in promoting SCFA biosynthesis (Clarke et al.,
2014; Dumas et al., 2017; Murtaza et al., 2019). Consistent with
this observation, the implementation of a training program that
combined aerobic and resistance exercise resulted in an increased
abundance of Blautia, Dialister, and Roseburia, and decreased
abundance of Proteobacteria and Gammaproteobacteria phylum
in obese children (Quiroga et al., 2020). However, 12 weeks
into the intervention, no differences in gut microbiota profile
were detected between the obese children and an age-matched,
healthy control cohort.
A bidirectional relationship between exercise and bacterial
strains has been reported in older adults supplemented with
Lactobacillus casei, which was associated with increased physical
activity levels as measured via daily step count (Aoyagi
et al., 2019). Observational data reveal that physically active
older adults are characterized by an increased abundance of
Bifidobacteriales and Clostridiales species (Castro-Mejía et al.,
2020). This observation is not consistent with previous studies
that indicated a decreased microbial diversity during sedentarism
(Bressa et al., 2017; Castellanos et al., 2020). Moreover,
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Prokopidis et al.
Anabolic Resistance and Gut Microbiota
together, these preliminary findings indicate that resistance
exercise may lead to the production of SCFA metabolites,
contributing to improved muscle strength, although this thesis
warrants direct investigation in older adults. Future studies
designed to examine the impact of resistance training on bacteria
taxa and SCFA production and their influence on the gut
microbiome in young and older adults would provide more
reliable conclusions in humans.
differences in bacteria taxa have been observed through
higher Faecalibacterium prausnitzii and lower Parasutterella
excrementihominis between physically active and communitydwelling older adults (Fart et al., 2020). However, limited data
in humans has been generated regarding the modulation of gut
microbiota with resistance training in older adults.
Although endurance exercise confers multiple metabolic
health benefits, including improved insulin sensitivity,
mitochondrial function, and maximal oxygen consumption (Bird
and Hawley, 2017; Hargreaves and Spriet, 2020), resistance
training provides the most robust anabolic stimulus to
mitigate age-related AR (Mcleod et al., 2019). Preliminary
in vivo data suggest an improvement in gut microbiota
diversity and composition in response to resistance training
(Chen et al., 2021). Specifically, a previous study revealed
a reduced relative abundance of pro-inflammatory-induced
species, including Pseudomonas, Serratia, Comamonas, and
Firmicutes/Bacteroidetes ratio that translated to a decrease in
intestinal mucosal permeability and enriched SCFA-producing
gut microbiota. Whereas no changes in the gut microbiome
with resistance training were observed in young adults
(Bycura et al., 2021), this study may be considered to lack
statistical power in terms of microbiome sampling, and the
short duration of intervention (8 week) implemented may
have been insufficient to elicit detectable changes in the gut
microbiome (Bycura et al., 2021). Interestingly, a seminal
study by Fielding et al. (2019) revealed that transferring fecal
samples from high-functioning older adults to mice increased
the abundance of Barnesiella intestinihominis bacteria that
corresponded with improved grip strength compared with lowfunctioning-colonized mice (Fielding et al., 2019). Indeed, the
high-functioning-colonized mice displayed a higher number
of Prevotellaceae family, Prevotella and Barnesiella genus,
and Barnesiella intestinihominis species compared to lowfunctioning-colonized mice. These findings align with previous
work linking an elevated Prevotellaceae family profile to young
professional athletes (Clarke et al., 2014), and Prevotella and
Barnesiella to less frail phenotypes (Van Tongeren et al., 2005;
Claesson et al., 2012; Verdi et al., 2018). Accordingly, these
data suggest that these microbes are associated with better
physical conditioning. Moreover, genes derived from Barnesiella
and Prevotellaceae may produce SCFAs, that could further
explain the improved muscle functional outcomes germ-free
mice following a SCFA cocktail (Lahiri et al., 2019). Taken
CONCLUSION
Preliminary evidence, based on a limited number of hypothesisdriven studies primarily conducted using animal models,
suggests a mechanistic action for the gut microbiota in
countering age-related AR and sarcopenia risk. However, at
present, clinical trials are warranted to validate these microbialinduced outcomes on skeletal muscle using in vivo human
models. Based on findings from animal- and cell-based models,
there is evidence to suggest that improvements in de novo amino
acid biosynthesis may correspond with the maintenance of gut
microbiota diversity through promotion of SCFA via dietary fiber
and protein consumption. Moreover, in vivo experiments have
demonstrated an increased SCFA production following exercise
that may attenuate AR by enhancing amino acid utilization and
reducing levels of low-grade inflammation. Moving forward,
the design of lifestyle approaches that combine increased
dietary fiber and protein intake, probiotic supplementation and
resistance training may be effective in optimizing gut microbiota
composition with implications for muscle health in older adults
at risk of sarcopenia.
AUTHOR CONTRIBUTIONS
KP and OW conceived and wrote the initial draft of the
manuscript. EC and MN reviewed and revised the manuscript.
All authors contributed to the article and approved the
submitted version.
ACKNOWLEDGMENTS
Figures were created with BioRender.com.
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